Project Summary/Abstract Pulmonary arterial hypertension (PAH) is a highly morbid pulmonary vascular disease that is the leading cause of death in patients with systemic sclerosis (SSc). SSc patients with PAH have a three year survival estimate of 56%, compared to 94% in SSc patients without PAH. Little is known of the genetic or molecular determinants of PAH development in the context of SSc. Consequently, there are few mechanistic biomarkers of disease risk available to aid in early detection, and the majority of patients are diagnosed late in the disease course. Our preliminary data suggest that serum uric acid (UA) predicts PAH development in patients with SSc and is associated with disease severity and survival in SSc-PAH, thereby making it an attractive candidate biomarker. UA is generated by the enzyme xanthine oxidoreductase (XOR), a product of the gene XDH that has been implicated in a variety of cardiopulmonary diseases. Increased XOR activity has been measured in the serum of patients with idiopathic PAH, and our preliminary data show that genetic variants in XDH are associated with more severe disease and worse outcomes in SSc-PAH. We hypothesize that serum UA is a surrogate marker of XOR enzymatic activity, and that XOR is a modifier of risk and disease severity in SSc-PAH. We further hypothesize that differential XOR expression or activity may be driven by variants in XDH. This proposal has two novel aims. First, to demonstrate that XOR and its metabolite UA are mechanistic biomarkers of PAH risk and severity in SSc, we will measure XOR protein concentrations, XOR enzymatic activity, and UA levels in the serum of SSc patients with and without PAH. Using a nested case-control design, we will investigate elevated UA and XOR levels as possible risk factors for PAH in SSc. In a separate cohort, we will examine associations between UA/XOR levels and SSc-PAH disease severity and survival. Second, we will define relationships between genetic variants in XDH and clinical phenotypes and outcomes in SSc-PAH patients. Successful completion of these aims would support the use of UA as a diagnostic and prognostic mechanistic biomarker in SSc-PAH, and may implicate XOR as a potential targetable modifier of risk and disease severity. If we find that an upregulated XOR/UA pathway confers increased PAH risk in SSc, we may be able to identify and treat disease earlier and explore new therapeutic targets, which may ultimately improve outcomes in SSc-PAH.